This invention relates to a new class of azole derivatives, methods for their use, and processes for their production. The compounds described herein are useful for the treatment of fungal infections in humans and other mammals. The present invention provides a compound represented by the general formula 
wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, n is 0 or 1, and R1 and R2 are hydrogen, C1-C6 alkyl or C2-C6 alkenyl, said alkyl or alkenyl group being optionally substituted by a hydroxy or dimethylamino group, or R1 and R2 taken together with the nitrogen to which they are attached forms a heterocyclic group of the formula 
where R7 is hydrogen, CHO, COR13 or C1-C6 alkyl in which the alkyl group may be optionally interupted by an oxygen atom or NR14 and may be substituted by hydroxy, R8, R9, R10, R11 and R12 are each independently hydrogen, hydroxy, CONH2, or C1-C6 alkyl, said alkyl group being optionally substituted by hydroxy, R13 is C1-C6 alkyl and R14 is hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.
Triazole antifungal compounds are well known in the prior art. Of the several classes known, one particularly potent class contains a tertiary hydroxyl group. For example, U.S. Pat. No. 5,648,372 discloses that (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol has anti-fungal activity. 
The utility of this class of compounds is limited by their low water solubility. One method of addressing this problem was disclosed in European Patent Application 829478, where the water solubility of an azole antifungal agent was increased by attaching a linked amino-acid to the azole portion of the molecule. 
Alternatively, WO 97/28169 discloses that a phosphate moiety can be attached directly to the tertiary hydroxyl portion of the anti-fungal compound, e.g. the compound having the formula 
Examples describing the use of N-N-dialkylaminomethyl benzoate derivatives as prodrugs can be found in H. Bundgaard et al, J. Med Chem. 32, 2503 (1989); E. Jensen et. al. Int. J. Pharmaceut. 58,143 (1990); and H. Bundgaard, Drugs of the Future 16, 443 (1991).
It has now been found that triazole anti-fungal compounds containing a secondary or tertiary hydroxyl group, including (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol, may be converted into prodrugs with superior properties to those previously disclosed by attaching an amino-containing moiety via a linking group. Specifically, the invention covers compounds of the formula: 
wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, n is 0 or 1, and R1 and R2 are hydrogen, C1-C6 alkyl or C2-C6 alkenyl, said alkyl or alkenyl group being optionally substituted by a hydroxy or dimethylamino group, or R1 and R2 taken together with the nitrogen to which they are attached forms a heterocyclic group of the formula 
where R7 is hydrogen, CHO, COR13 or C1-C6 alkyl in which the alkyl chain may be optionally interupted by either an oxygen atom or NR14 and may be substituted by a hydroxy group, R8, R9, R10, R11 and R12 are each independently hydrogen, hydroxy, CONH2 or C1-C6 alkyl, said R8, R9, R10, R11 or R12 alkyl group being optionally substituted by hydroxy, R13 is C1-C6 alkyl and R14 is hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, A represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary hydroxy group.
The various methylamine substituents of formula I may be attached in either an ortho, meta, or para relationship to the ester substituent, with the preferred attachment being either meta or para.
In a preferred embodiment A can be 
wherein R3 represents phenyl substituted by one or more (preferably 1-3) halogen atoms;
R4 represents H or CH3;
R5 represents H, or taken together with R4 may represent xe2x95x90CH2;
R6 represents a 5- or 6 membered nitrogen containing ring which may be optionally substituted by one or more groups selected from halogen, xe2x95x90O, phenyl substituted by one or more groups selected from CN, (C6H4)xe2x80x94OCH2CF2CHF2 and CHxe2x95x90CHxe2x80x94(C6H4)xe2x80x94OCH2CF2CHF2, or phenyl substituted by one or more groups selected from halogen and methylpyrazolyl.
Nitrogen containing heterocycles which R6 may represent include triazolyl, pyrimidinyl, and thiazolyl.
Specific examples of A include, but are not limited to, the following: 
In addition to the application of the present invention to structures containing a tertiary alcohol, it should also be understood that this discovery can be applied to anti-fungal agents which contain secondary alcohols. Some examples include, but are not limited to, the following: 
Representative R1, R2 and n values are shown below: 
(where A represents the non-hydroxy portion of a triazole anti-fungal compound of the type containing a tertiary or secondary hydroxyl group)
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein is intended to include the non-toxic acid addition salts with inorganic or organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p-toluene-sulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic, hydroiodic, hydrobromic, and the like.
The term xe2x80x9chalogenxe2x80x9d includes chloro, bromo, fluoro and iodo, and is preferably chloro or fluoro, and most preferably fluoro.
The aliphatic xe2x80x9calkylxe2x80x9d and xe2x80x9calkenylxe2x80x9d groups may be straight or branched chains having the specified number of carbon atoms, e.g. in the case of C1-C6 alkyl, the alkyl group may have from 1 to 6 carbon atoms.
Preferred embodiments of the present invention, including in each case pharmaceutically acceptable salts thereof are:
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N,N-diethylaminomethyl)benzoyloxy]methoxy]butane (compound of example 1)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N,N-di-(2-hydroxyethyl)aminomethyl) benzoyloxy]methoxy]butane (compound of example 2)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(4-methyl-piperazinyl)methyl]benzoyloxy]methoxy]butane (compound of example 3)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N,N-dimethylaminomethyl)benzoyloxy]methoxy]butane (compound of example 4)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N-methyl-N-(2-hydroxyethyl)aminomethyl) benzoyloxy]methoxy]butane (compound of example 5)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N-ethyl-N-butyl)aminomethyl]benzoyloxy]methoxy]butane (compound of example 6)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(4-(2-hydroxyethyl)-1-piperazinylmethyl) benzoyloxy]methoxy]butane (compound of example 7)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(3RS-hydroxy)-1-piperidinylmethyl]benzoyloxy]methoxy]butane (compound of example 8)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4-(2RS-hydroxyethyl)-1-piperidinylmethyl]benzoyloxy]methoxy]butane (compound of example 9)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)2-[[p-[(4-formyl)-1-piperazinylmethyl]benzoyloxy]methoxy]butane (compound of example 10)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4RS-hydroxy)-1-piperidinylmethyl]benzoyloxy]methoxy]butane (compound of example 11)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4-ethyl)-1-piperazinylmethyl]benzoyloxy]methoxy]butane (compound of example 12)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4RS-methyl)-1-piperidinylmethyl]benzoyloxy]methoxy]butane (compound of example 13)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4RS-(N-piperadinyl)-1-piperidinylmethyl]benzoyloxy]methoxy]butane (compound of example 14)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N,N-dipropyl)aminomethyl]benzoyloxy]methoxy]butane (compound of example 15)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(3RS-hydroxy)-1-pyrrolidinylmethyl]benzoyloxy]ethoxy]butane (compound of example 16)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N,N-diallyl)aminomethyl]benzoyloxy]methoxy]butane (compound of example 17)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(2S,6R-dimethyl-1-piperidinyl)methyl]benzoyloxy]methoxy]butane (compound of example 18)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[N-ethyl-N-(2-dimethylaminoethyl) aminomethyl]benzoyloxy]methoxy]butane (compound of example 19)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(3-thiazolidinyl)methyl]benzoyloxy]methoxy]butane (compound of example 20)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N-methyl-N-(3-dimethylaminopropyl) aminomethyl]benzoyloxy]methoxy]butane (compound of example 21)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(3RS-methyl-1-piperidinyl)methyl]benzoyloxy]methoxy]butane (compound of example 22)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[N-methyl-N-(2-dimethylaminoethyl) aminomethyl]benzoyloxy]methoxy]butane (compound of example 23)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[N,N-bis-(2RS-hydroxypropyl)aminomethyl]benzoyloxy]methoxy]butane (compound of example 24).
2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(1-piperidinyl)methyl]benzoyloxy]methoxy]butane (compound of example 25)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4-morpholinyl)methyl]benzoyloxy]methoxy]butane (compound of example 26)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-[(4-morpholinyl)methyl]benzoyloxy]methoxy]butane (compound of example 27)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-(N,N-diethylaminomethyl)benzoyloxy]methoxy]butane (compound of example 28)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-[N,N-bis(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]butane (compound of example 29)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-[(4-methyl-1-piperazinyl)methyl]benzoyloxy]methoxy]butane (compound of example 30)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[(4-morpholinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 31)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[N,N-diethylaminomethyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 32)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-morpholinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 33)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[N,N-bis-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 34)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[(4-methyl-1-piperazinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 35)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N,N-bis-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 36)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-methyl-1-piperazinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 37)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N,N-diethylaminomethyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 38)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-(2xe2x80x2-hydroxyethoxy)ethyl-1-piperazinyl) methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 39)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N-methyl-N-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 40)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4xe2x80x2-hydroxy-4-piperidinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 41)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4xe2x80x2-carbamyl-4-piperidinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 42)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2[[[m-[(4-(2-hydroxyethyl)-1-piperazinyl) methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 43)
The more preferred embodiments of the present invention, including in each case pharmaceutically acceptable salts thereof are:
1,2,4-triazol-1-yl)-2-[[p-[(4-morpholinyl)methyl]benzoyloxy]methoxy]butane (compound of example 26)
1,2,4-triazol-1-yl)-2-[[[p-[N,N-diethylaminomethyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 32)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-morpholiny)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 33)
1,2,4-triazol-1-yl)-2-[[[p-[N,N-bis-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 34)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N,N-b is-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 36)
1,2,4-triazol-1-yl)-2-[[[m-[N,N-diethylaminomethyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 38)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-(2xe2x80x2-hydroxyethoxy)ethyl-1-piperazinyl) methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 39)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N-methyl-N-(2-hydroxyethyl)aminomethyl]enzoyloxy]methoxy]carbonyloxy]butane (compound of example 40)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4xe2x80x2-hydroxy-4-piperidinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 41)
(2R,3R)-3-t4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4xe2x80x2-carbamyl-4-piperidinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 42)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-(2-hydroxyethyl)-1-piperazinyl) methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 43).
The aforementioned preferred embodiments of the present invention are listed in the table below along with their observed molecular ions (M+ or MH+). 
The compounds of the present invention can be made by conventional methods. Two suitable procedures are summarized by the following reaction schemes. In both methods, A represents the non-hydroxy portion of a triazole anti-fungal compound of the type containing a tertiary or secondary hydroxy group. 
X=Cl, Br or I, preferably Cl 
To elaborate on Method 1, the anti-fungal parent compound of interest is converted into ester 2 by reaction with chloride 1 in the presence of a suitable base, such as potassium hydride. The reaction can be carried out in THP or other appropriate solvent and the product is usually purified by column chromatography. Chloride 1 can be prepared by the general method of Iyer et al., Syn. Comm. 25, 2739, 1995 (see Method 1 below in the Illustrative Examples section) or by Method 2 shown below in the Examples). Ester 2 can be subsequently transformed into arylmethylamine 3 by reaction with the desired dialkyl amine in DMF. The reaction occurs between 25xc2x0 C. and 100xc2x0 C. and the resulting product can be purified by recrystallization or column chromatography. If an amine salt is used, it will be understood that one molar equivalent of an appropriate base should be added to facilitate the reaction.
The intermediates 2 of the formula 
wherein the halomethyl substituent is in the ortho, meta or para position, preferably the meta or para position, X is chloro, bromo or iodo, preferably chloro, and A represents the non-hydroxyl portion of a triazole antifungal compound of the type containing a tertiary or secondary hydroxyl group are another aspect of the present invention. The preferred intermediates are those having the specific xe2x80x9cAxe2x80x9d groups mentioned above.
The intermediates 2 may be prepared by reacting a suitable halomethyl benzoic acid ester of the formula 
wherein the halomethyl substituent of the phenyl ring is in the ortho, meta or para position, preferably the meta or para position, X is Cl, Br or I, and A represents the non-hydroxyl portion of a triazole antifungal compound of the type containing a tertiary or secondary hydroxyl group with an antifungal agent Axe2x80x94OH wherein A is as defined above in an inert organic solvent such as tetrahydrofuran and in the presence of base such as potassium hydride.
To elaborate on Method 2, the anti-fungal parent compound of interest is transformed into chloromethylformate 4 by reaction with commercially available chloromethylchloroformate (Aldrich Chemical Company) in the presence of an appropriate base in THF or other solvent at 0xc2x0 C. to 50xc2x0 C. Appropriate bases include potassium hydride and sodium hydride, among others, with the preferred base being potassium hydride. The product can be purified by column chromatography. Chloromethylformate 4 is converted to iodide 5 by reaction at elevated temperature with NaI in acetone. The crude product from this reaction can be used in the next step, or the product can be purified via column chromatography. In another aspect then, the present invention provides intermediates 4 of the formula 
wherein X1 is Cl, Br or I and A is the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary or secondary hydroxyl group. The preferred intermediates of formula 4 are those having the specific xe2x80x9cAxe2x80x9d groups mentioned above. Intermediates 4 may be prepared by reacting chloromethylchloroformate with an antifungal agent Axe2x80x94OH in which A is as defined above in an inert organic solvent such as tetrahydrofuran. in the presence of base and, if desired, converting the so-produced chloromethylformate of formula 4 to the corresponding compound of formula 4 wherein X1 is Br or I by reaction with an alkali metal bromide or iodide. Iodide 5 is converted to the final product 7 by reaction with carboxylate salt 6 in acetonitrile or other appropriate organic solvent. The efficiency of the reaction can be increased by adding small amounts of 18-crown-6 or other appropriate crown ether. Carboxylate salt 6 can be prepared by the method disclosed in Lombardino et al in U.S. Pat. No. 4,623,486. The product can be purified by recrystallization or column chromatography. If an amine salt is used, it will be understood that one molar equivalent of an appropriate base should be added to facilitate the reaction. It is also possible to directly convert chloride 4 to the final product by reaction with carboxylate salt 6 at elevated temperatures.
It will be understood that where the substituent groups used in the above reactions contain certain reaction-sensitive functional groups such as amino or carboxylate groups which might result in undesirable side-reactions, such groups may be protected by conventional protecting groups known to those skilled in the art. Suitable protecting groups and methods for their removal are illustrated, for example, in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley and Sons, 1991). It is intended that such xe2x80x9cprotectedxe2x80x9d intermediates and end-products are included within the scope of the present disclosure and claims.
The desired end-product of formula I may be recovered in the form of a pharmaceutically acceptable acid addition salt, e.g. by addition of the appropriate acid such as HCl, HI or methane-sulfonic acid to the amine.
It will be appreciated that certain products within the scope of formula I may have substituent groups which can result in formation of optical isomers. It is intended that the present invention include within its scope all such optical isomers as well as epimeric mixtures thereof, i.e. R- or S- or racemic forms.
The pharmaceutically active compounds of this invention may be used alone or formulated as pharmaceutical compositions comprising, in addition to the active triazole ingredient, a pharmaceutically acceptable carrier, adjuvant or diluent. The compounds may be administered by a variety of means, for example, orally, topically or parenterally (intravenous or intramuscular injection). The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. Compositions for injection may be prepared in unit dose form in ampules or in multidose containers and may contain additives such as suspending, stabilizing and dispersing agents. The compositions may be in ready-to-use form or in powder form for reconstitution at the time of delivery with a suitable vehicle such as sterile water.
Alternatively, the compounds of the present invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, or cream. Additionally, they may be incorporated (at a concentration up to 10%) into an ointment consisting of a white wax or soft, white paraffin base together with the required stabilizers and/or preservatives.
The compounds of the invention are useful because they possess pharmacological activities in animals, including particularly mammals and most particularly, humans. Specifically, the compounds of the present invention are useful for the treatment or prevention of topical fungal infections, including those caused by species of Candida, Trichophyton, Microsporum, or Epidermophyton. Additionally, they are useful for the treatment of mucosal infections caused by Candida albicans. They can also be used in the treatment of systemic fungal infections caused, for example, by species of Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, Coccidioides, Paracoccidiodes, Histoplasma, or Blastomyces.
Thus, according to another aspect of the invention, there is provided a method of treating a fungal infection which comprises administering a therapeutically effective amount of the compound to a host, particularly a mammalian host and most particularly a human patient. The use of the compounds of the present invention as pharmaceuticals and the use of the compounds of the invention in the manufacture of a medicament for the treatment of fungal infections are also provided.
The dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 5 mg/day to about 1.0 g/day. These doses are exemplary of the average case, and there can be individual instances where higher or lower dosages are merited, and such dosages are within the scope of this invention. Furthermore, administration of the compounds of the present inventions can be conducted in either single or divided doses.
The in vitro evaluation of the antifungal activities of the compounds of the invention can be performed by determining the minimum inhibitory concentration (MIC). The MIC is the concentration of test compound which inhibits the growth of the test microorganism. In practice, a series of agar plates, each having the test compound incorporated at a specific concentration, is inoculated with a fungal strain and each plate is then incubated for 48 h at 37xc2x0 C. The plates are examined for the presence or absence of fungal growth, and the relevant concentration is noted. Microorganisms which can be used in the test include Candida albicans, Asperigillus fumigatus, Trichophyton spp., Microsporum spp., Epidermophyton floccosum, Coccidioides immitis, and Torulopsos galbrata. It should be recognized that, as prodrugs, some compounds of the invention may not be active in the in vitro test.
The in vivo evaluation of compounds of the present invention can be carried out at a series of dose levels by intraperitoneal or intravenous injection or by oral administration to mice which have been inoculated with a strain of fungus (e.g. Candida albicans). Activity is determined by comparing the survival of the treated group of mice at different dosage levels after the death of an untreated group of mice. The dose level at which the test compound provides 50% protection against the lethal effect of the infection is noted.
The compounds of the present invention substantially increase the solubility of the parent triazole antifungal compound and also release the bioactive parent compound (i.e. function as a prodrug) in both rat and human plasma. As shown in the table below, this is not the case with the triazole derivatives of WO 97/28169.